Template talk:Amphetamine base in marketed amphetamine medications

Dyanavel label

The prescribing information for Dyanavel includes a section (2.3 Switching from other Amphetamine Products) which indicates that this product shouldn't be substituted with other products on the basis of amphetamine base mass in each product. The composition issue isn't that significant since this is really just a determinant of an IR vs an XR dosage form (it's fairly intuitive that IR doses are comparable to IR, but not XR, and vice versa). The notable issue is that the base pharmaceutical has a higher bioavailability relative to the salt pharmaceuticals, the latter of which has a pH-dependent bioavailability. The Dyanavel prescribing info doesn't appear to indicate that the bioavailability of that product is pH-dependent.

Given these 2 differences in bioavailability, an equipotent dose for the base and the salts will not be accurate; this is because an implicit assumption in the computation of those values is that the bioavailability is the same for all of the products listed. That's likely the main reason the prescribing information included that section. In any event, I'm not sure how you want to deal with that, but the only two solutions are basically just cut the equipotent doses column or remove the entry for the Dyanavel row. Seppi333 (Insert 2¢) 20:22, 11 December 2015 (UTC)

Come to think of it, I just remembered that this is the same issue with lisdexamfetamine: it's absorbed as the prodrug which doesn't have the same pH-dependent bioavailibility as d-amphetamine. This is covered in Amphetamine#Pharmacokinetics. That's the only other amphetamine product with distinct absorption kinetics. Seppi333 (Insert 2¢) 20:52, 11 December 2015 (UTC)

Part of the 2.3 Switching... warning is simply about the base content in salts being different from the pure base in Dyanavel. The "differing pharmacokinetic profiles" has to do with the relative bioavailability curve being different. See page 16-17 of Tris' Pharmacology & Biopharmaceutics Review for Dyanavel. Being that Cmax is considered equivalent I'm inclined to let this stand for now, at least until we can resolve it a bit. Looking at the curve on p 17, my impression is the Tris mechanism may be abuse resistant but isn't great at time release. It tends to release a bolus of the active ingredient. If the Adderall was given in a single dose, or an hour apart, or 80% immediately and 20% at 4 hours, the curve and bioavailability would be extremely close. It's not as much about the pH as the delivery mechanism. The only thing is says remotely related to pH is that amphetamine has a pKa of 9.9.

I am interested in the lisdexamfetamine issue. My eyes are blurry and I had a crash writing this so I'll look at this and follow up tomorrow.

I looked at addiction research and concede that you are right about including sensitization. — Box73 (talk) 13:15, 12 December 2015 (UTC)

The pharmacokinetics of lisdexamfetamine and different salts of amphetamine differ somewhat. Lisdexamphetamine is much less effected by gastrointestinal pH than dextro/amphetamine salts, yet lisdexamphetamine has a slower release (conversion) into dextroamphetamine, profoundly at supertheraputic doses where it is thought to saturate the available enzymes. But differences found in studies at supratheraputic doses (60mg/kg) or IV administration need not be considered.

However lisdexamfetamine's NDA documents say, "The AUC and Cmax for d-amphetamine from 75 mg NRP104 (lisdexamfetamine) were comparable to both d-amphetamine and l-amphetamine from 35 mg Adderall XR." Elsewhere it says, "As for AUC values for d-amphetamine base following oral administration of NRP-104, they were comparable to those observed after oral administration of d-amphetamine sulfate at lower doses". (Lower doses here would refer to those used therapeutically.) See documents at FDA Approval Package for Vyvanse.

I suggest the equipotent doses columns be retitled as ideal equipotent dosages, with an explanation in the notes. Do you feel this is reasonable? Is there a way to accommodate both of our concerns? I appreciate your insight and frankness. — Box73 (talk) 02:53, 14 December 2015 (UTC)

Optional comments. (1) An equipotent table of opioids list the prodrug codeine and (semi-)prodrug hydrocodone which are CYP-2D6-dependent; here typical biology is assumed. (2) My concern is what the Dyanavel monograph warns about a milligram-to-milligram conversion of the pharmaceutical compounds, not the active base. Adderall and Evekeo use the same dosing as Dexedrine, making the assumption of equipotency. (The Dexedrine dosing for ADHD was set when it was only treated in children, yet continues in the forms approved for adult ADHD.) Re narcolepsy, Adderall and Evekeo use the same dosing as Dexedrine though as you have said, levo is much less centrally stimulating than dextro. (3) The potency information is actually already present in the listed base content of the medications. Yet it becomes perceptible and meaningful when presented as a reciprocal. (4) These must not be seen simply as a single dose equivalence and are not directly practical. Further a practical table might also list equipotent doses of other stimulants, viz, methylphenidate, dexmethylphenidate and methamphetamine; this clearly advises and violates MOS guidelines. — Box73 (talk) 02:53, 14 December 2015 (UTC)

My sole concern at this point isn't that the content isn't accurate (since it's now stated as such); it's that it's making enough assumptions that other editors/readers would consider it OR, especially given that this content is in several articles. While I appreciate the utility of the information that column provides, it's computed entirely based upon a series of assumptions that we have made. I honestly think we should seek input from other editors on this before we proceed. If there's no concern, I'm ok with transcluding this template into any remaining articles. Seppi333 (Insert 2¢) 23:21, 15 December 2015 (UTC)

Edit: I'm referring exclusively to the last column in the prior statement. The rest I think is perfectly suitable for articles. Seppi333 (Insert 2¢) 23:27, 15 December 2015 (UTC)

I hear you: the equivalent doses column(s). The differing and complex pharmacokinetics make equivalency difficult, and multiple assumptions raise OR issues. Equivalency differs from the base content which is objective and independent of pharmacokinetics. (Equivalent doses, although a reciprocal of the base content, leads readers/editors to assume a single dose with the same duration and effect, which isn't true.)

Medical literature generally refers to total daily doses to provide equivalency. This might bring us closer to a solution. It reduces pharmacokinetic issues. Rounding or reducing significant digits would help. This should result in ideal values that are reasonably accurate. For comparison, consider the Equianalgesic table which gives rounded single doses of different drugs with various pharmacokinetics. Assumptions are made when Methadone has 40%-90% bioavailability but a single value of 3.33mg is given as an equivalent dose of 10mg (IV) of morphine. Practically, all of this is ideal since FDA considers equivalency to be 80%-125% of AUC and Cmax of the reference drug values.

Having said that, your issue remains the unique PKs of lisdexamfetamine and amphetamine base suspension. On the scale of a day would these differences average out?

Lastly, I'm worried about confusing readers with the x - 4x values. If equivalency stays perhaps a single column with a range might read better.

I respect your views and increasingly so. Let me take a crack at one last modification of those columns tomorrow and go from there. I am teetering... — Box73 (talk) 09:03, 17 December 2015 (UTC)

I think there's less of an issue about accuracy now, but I still feel we should get wider input on that column of data about whether or not it's perceived as OR. If you're willing, we can seek input frpm the med/pharm wikiprojects. Seppi333 (Insert 2¢) 15:45, 20 December 2015 (UTC)

I'm willing. I've been surfing for up to date amphetamine equivalence material. The only thing I've found thus far was one psychiatrist's presentation which had several errors, besides not being a reliable source. — Box73 (talk) 13:16, 21 December 2015 (UTC)

Alright, I'll post a thread on the two project talk page right after the new year (January 1st or 2nd). Based upon past experience, many active editors (me included) tend to take a break from WP over the holidays so I wouldn't expect much feedback until afterward anyway. Seppi333 (Insert 2¢) 21:08, 22 December 2015 (UTC)

I understand. Before presenting the issue, see my changes. I changed from "equipotent dose"/"equivalent daily dosage" to "dose with equivalent equal base content", simplified the column and clarified that the values do not represent equipotent doses due to PK (and enantiomer) issues. ("Equivalent" could be "equal" base content. so changed) Hopefully this will resolve OR concerns. I appreciate your critique and cooperation. Have a Merry Christmas and Happy New Year! — Box73 (talk) 02:56, 24 December 2015 (UTC) ...revised — Box73 (talk) 08:03, 25 December 2015 (UTC)

Yeah, looks perfectly fine to me now; I don't see this being an OR issue for anyone anymore. Also, the last column can include a mass unit now since it's no longer comparing pharmacological activity.

Happy holidays. Seppi333 (Insert 2¢) 17:46, 25 December 2015 (UTC)

Formatting and note tweaks + transclusion

I made some tweaks to the notes and fixed various formatting issues:

• I changed the citation formatting to avoid redundant reference definitions and ensure that the web citation formatting was consistent with the formatting used in the articles where this template is currently transcluded.
• I deleted 2 notes that didn't seem relevant to the current table data. I don't think the note on the table title is necessary since what it says is readily apparent; instead of deleting it, I simply removed it from 1 transclusion.
• Barring some minor issues (sentences w/o refs, MOS formatting, grammar, etc), the other notes were fine.

That said, I have no concerns with anything in the table now so I replaced the table in the amph article with this template. Seppi333 (Insert 2¢) 11:38, 1 January 2016 (UTC)